Derivatives of 7 alkynyl-1,8 naphthyridones, preparation method thereof and use of same in therapeutics

ABSTRACT

The disclosure relates to method of treating a disease in which VEGFR-3 is involved, comprising administering a therapeutically effective amount of a compound of the formula 
                         
wherein R 1 , R 2 , R 3 , and R 4  are as defined in the disclosure, to compositions containing them, to processes for preparing them, and to their use in therapeutics.

This application is a divisional of U.S. patent application Ser. No.12/631,130 filed Dec. 4, 2009, which is a continuation of InternationalApplication No. PCT/FR2008/000794 filed Jun. 11, 2008, the entirecontents of which are incorporated herein by reference

The present invention relates to 7-alkynyl-1,8-naphthyridonederivatives, to their preparation and to their therapeutic application.

A subject matter of the present invention is compounds corresponding tothe formula (I):

in which:

-   -   R₁ and R₂ represent, independently of one another:        -   a hydrogen atom,        -   a C₁-C₇ alkyl group optionally substituted by one or more            alkoxy groups,    -   R₃ represents a C₁-C₇ alkyl group,    -   R₄ represents a hydrogen atom or a C₁-C₄ alkyl group,    -   Y represents a C₁-C₄ alkoxy group or an —NRR′ or        —O(CH₂)_(n)—C(O)—NRR′ group where R and R′ are as defined below        and n is an integer equal to 1 or 2,    -   R″ represents a C₁-C₄ alkyl group, and    -   R and R′ represent, independently of one another, a hydrogen        atom, a —CO—(C₁-C₄ alkyl) group or a —COOR″ group, where R″ is        as defined above.

The compounds of formula (I) can comprise one or more asymmetric carbonatoms. They can therefore exist in the form of enantiomers ordiastereoisomers. These enantiomers, diastereoisomers and their mixture,including their racemic mixture, come within the invention.

The compounds of formula (I) can exist in the form of bases or salifiedby acids or bases, in particular pharmaceutically acceptable acids orbases. Such addition salts come within the invention. These salts areadvantageously prepared with pharmaceutically acceptable acids or basesbut the salts of other acids or bases, for example of use in thepurification or the isolation of the compounds of formula (I), also comewithin the invention.

The compounds according to the invention can also exist in the form ofhydrates or solvates, namely in the form of combinations or associationswith one or more molecules of water or with a solvent. Such hydrates andsolvates also come within the invention.

In the context of the present invention and unless otherwise mentionedin the text:

-   -   an alkyl group is understood to mean a saturated, linear or        branched, aliphatic group comprising from 1 to 7 carbon atoms        (advantageously from 1 to 4 carbon atoms). Mention may be made,        as examples, of the methyl, ethyl, propyl, isopropyl, butyl,        isobutyl, tert-butyl, pentyl, hexyl or heptyl groups, and the        like;    -   an alkoxy group is understood to mean an —O-alkyl group, where        the alkyl group is as defined above;    -   a halogen atom is understood to mean a fluorine, a chlorine, a        bromine or an iodine.

Mention may be made, among the compounds which are a subject matter ofthe invention, of a subgroup of compounds for which Y represents a C₁-C₄alkoxy group.

Mention may be made, among the compounds which are a subject matter ofthe invention, of a second subgroup of compounds for which Y_representsan —NRR′ group where R and R′ are as defined above.

Mention may be made, among the compounds which are subject matters ofthe invention, of a third subgroup of compounds for which Y representsan —O(CH₂)_(n)—C(O)—NRR′ group where R and R′ are as defined above and nis an integer equal to 1 or 2.

Mention may in particular be made, among the compounds which are subjectmatters of the invention, of the following compounds:

-   methyl    {3-[7-amino-8-ethyl-6-(methylcarbamoyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-yl]prop-2-yn-1-yl}carbamate-   2-amino-7-(3-amino-3-methylbut-1-yn-1-yl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide    hydrochloride-   (±)-2-amino-7-(3,4-dimethoxy-3-methylbut-1-yn-1-yl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide-   2-amino-7-[3-(2-amino-2-oxoethoxy)-3-methylbut-1-yn-1-yl]-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide-   2-amino-1-ethyl-7-(3-methoxyprop-1-yn-1-yl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide.

In accordance with the invention, the compounds of formula (I) can beprepared according to the process presented in scheme 1.

According to scheme 1, a 2,6-dihalonicotinic acid of formula (II), wherethe X groups represent halogen atoms (preferably chlorine or bromine),which is either commercially available or prepared according to methodsknown to a person skilled in the art, is monosubstituted at the 2position by an amine of formula R₃—NH₂ (where R₃ is as defined above inconnection with the compounds of formula (I) which are subject mattersof the invention), at a temperature of between 20° C. and 150° C., in aprotic solvent, such as an alcohol or water, and optionally in a sealedtube. A 2-aminonicotinic derivative of formula (III) is obtained, whichderivative is converted to the acid fluoride of formula (IV) by theaction of cyanuric fluoride at ambient temperature, in the presence of abase, such as triethylamine or pyridine, and in an inert solvent, suchas dichloromethane, as described by G. Olah et al. in Synthesis (1973),487, or by other methods known to a person skilled in the art, such asthose described by Mukaiyama and Tanaka in Chem. Lett. (1976), 303, orby Ishikawa and Sasaki in Chem. Lett. (1976), 1407. The acyl fluoridesof formula (IV), which are highly reactive but stable, are subsequentlyreacted with an N-substituted cyanoacetamide of formula (V) in thepresence of a strong base, such as sodium hydride, in a polar aproticsolvent, such as dimethylformamide.

When two equivalents of sodium hydride are employed in the stage ofcondensation of the derivative (IV) with a derivative (V) and then athird equivalent of NaH is introduced after stirring at ambienttemperature for between 10 and 16 hours, the deprotonated compound (VI)formed cyclizes in situ at the same temperature with good yields todirectly provide the aminopyridino[2,3-b]pyridone of formula (VII)(method B).

The N-alkylcyanoacetamides of formula (V) are prepared by reactingcyanoacetic acid with an alkyl chloroformate (such as ethyl or isobutylchloroformate) in the presence of a base, such as triethylamine, at atemperature of less than or equal to 0° C., and then the mixed anhydrideintermediate formed is reacted with an excess of amine of formula R₄—NH₂(where R₄ is as defined above in connection with the compounds forformula (I) which are subject matters of the invention).

In order to obtain a pyridino[2,3-b]pyridinone of formula (I) which is asubject matter of the present invention, the halogenated intermediate offormula (VII) is coupled, according to the methods known to a personskilled in the art, with an appropriate derivative of propargyl alcoholR₁R₂CH(Y)CCH of formula (VIII), where R₁, R₂ and Y are as defined forthe compounds of formula (I). For example, the intermediate (VII) isinvolved in a Sonogashira coupling reaction with the appropriate alkyneof formula (VIII) in the presence of PdCl₂(PPh₃)₂, copper iodide,triethylamine and dimethylformamide at a temperature of between 80° C.and 120° C. This reaction can be carried out in a sealed tube and undermicrowave radiation.

If necessary, during the reaction stages presented in scheme 1, certainreactive functional groups situated on the Y, R₁, R₂ and R₃ groups canbe temporarily protected by protective groups known to a person skilledin the art, such as described in “Protective Groups in OrganicSynthesis”, Green et al., 2nd edition (John Wiley & Sons Inc., NewYork).

In scheme 1, the starting compounds and their reactants, when theirmethod of preparation is not described, are available commercially ordescribed in the literature or else can be prepared according to methodswhich are described therein or which are known to a person skilled inthe art.

Another subject matter of the invention, according to another of itsaspects, is the compounds of formula (VII) defined in scheme 1. Thesecompounds are of use as intermediates in the synthesis of the compoundsof formula (I).

The following examples illustrate the preparation of some compounds inaccordance with the invention. These examples are not limiting and serveonly to illustrate the present invention. The numbers of the compoundsgiven in the examples refer to those given in the table below, in whichthe chemical structures and the physical properties of a few compoundsaccording to the invention are illustrated.

EXAMPLE 1(±)-2-Amino-7-(3,4-dimethoxy-3-methylbut-1-yn-1-yl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(compound No. 1) 1.1: 2-(Ethylamino)-6-chloronicotinic acid

A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 mlof a 70% solution of ethylamine in water is stirred at ambienttemperature for 72 hours. The excess amine is then evaporated underreduced pressure and then a 10% aqueous acetic acid solution is addeduntil the product precipitates. The beige solid is filtered off, rinsedwith cold water and dried in an oven. 10.5 g of the expected product areobtained. Melting point: 158-160° C. Yield=62%.

1.2: 2-(Ethylamino)-6-chloronicotinic acid fluoride

2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol)of 2-(ethylamino)-6-chloronicotinic acid in 125 ml of dichloromethane.The mixture is stirred at ambient temperature for 3 hours and thenfiltered. The solid is rinsed with 50 ml of dichloromethane and thefiltrate is washed twice with 60 ml of ice-cold water. The organic phaseis dried over Na₂SO₄ and the solvent is evaporated under reducedpressure. 5.01 g of product are obtained in the form of an orange oil.Yield=99%.

1.3: N-Methylcyanoacetamide

12.28 ml (128.44 mmol) of ethyl chloroformate are added dropwise to asolution, cooled to −30° C., of 10.0 g (116.38 mmol) of 99% cyanoaceticacid and 16.3 ml (116.9 mmol) of triethylamine in 100 ml of anhydrousTHF and then the mixture is stirred at −30° C. for one and a half hours.300 ml of methanol saturated with gaseous methylamine are subsequentlyadded dropwise and then the mixture is stirred at ambient temperatureovernight. The solvents are evaporated under reduced pressure and theproduct is purified by filtration through silica gel, the elution beingcarried out with a dichloromethane:methanol (95:5) mixture. 10.0 g ofproduct are obtained in the form of a beige solid. Melting point=99° C.Yield=87%.

Method A (Parts 1.4 and 1.5 Below) 1.4:3-[6-Chloro-2-(ethylamino)-3-pyridinyl]-2-cyano-3-hydroxy-N-methyl-2-propenamide

3.98 g (100 mmol) of 60% sodium hydride in mineral oil are added insmall amounts to a solution, cooled to 0-5° C., of 9.80 g (100 mmol) ofN-methylcyanoacetamide in 100 ml of anhydrous dimethylformamide. Afterhydrogen has finished being given off, the mixture is stirred at ambienttemperature for 10 minutes and is then again cooled to 0-5° C. Asolution of 10.09 g (49.8 mmol) of 2-(aminoethyl)-6-chloronicotinic acidfluoride in 60 ml of dimethylformamide is then added and the medium isstirred at ambient temperature overnight. 2.85 ml (49.8 mmol) of aceticacid are added and the volatile materials are evaporated under reducedpressure. The residue is taken up in water and the product is extractedtwice with a dichloromethane:methanol (95:5) mixture and then once withan ethyl acetate:THF (2:1) mixture. The combined organic phases aredried over MgSO₄ and then the solvents are evaporated under reducedpressure. 19.0 g of product are obtained, which product is used as is inthe following stage.

1.5:2-Amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

A solution of 19.0 g of the crude product obtained on conclusion ofstage 7.4 (49.8 mmol) in 600 ml of n-butanol is heated at 110° C. for 48hours. The solvent is evaporated under reduced pressure and the solidobtained is triturated from methanol. The solid is subsequently filteredoff and dried in an oven. 7.9 g of the expected product are obtained inthe form of a pale yellow solid. Melting point: 283-286° C. Yield=57%.

Method B (Part 1.6 Below Instead of 1.4 and 1.5) 1.6:2-Amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

0.394 g (9.95 mmol) of 60% sodium hydride in mineral oil is added insmall amounts to a solution, cooled to 0-5° C., of 0.483 g (4.93 mmol)of N-methylcyanoacetamide in 7 ml of anhydrous dimethylformamide.Stirring is continued at this temperature for 10 minutes and then asolution of 1.0 g (4.93 mmol) of 2-(aminoethyl)-6-chloronicotinic acidfluoride in 5 ml of dimethylformamide is added. The medium is stirredovernight at ambient temperature and then a further 0.197 g (4.93 mmol)of 60% sodium hydride is added in small amounts. Stirring is continuedat this temperature for 10 minutes and then 0.56 ml (9.78 mmol) ofacetic acid is added. 60 ml of water are subsequently added and thesolid is filtered off, rinsed with water and then dried in an oven. 1.30g of the expected product are obtained. Melting point: 283-284° C.MH⁺=281. Yield=94%.

¹H NMR (d₆-DMSO, 400 MHz, δ in ppm): δ 11.75 (s, <1H, very broad); 11.00(q, 1H, broad); 8.45 (d, 1H); 8.10 (s, 1H, broad); 7.40 (d, 1H); 4.40(q, 2H); 2.80 (d, 3H); 1.25 (t, 3H).

1.7: Preparation of (±)-3,4-dimethoxy-3-methylbut-1-yne

1400 ml (0.7 mol) of a 0.5M commercial solution of ethynylmagnesiumchloride (or bromide) in tetrahydrofuran are run into a three-neckedflask under argon. Cooling is carried out to 2° C. with an ice bath andthe solution of 30 g (0.327 mol) of methoxyacetone in 600 ml oftetrahydrofuran is slowly added (exothermic). Stirring is carried out at2° C. for 1 hour and then the reaction mixture is poured onto anice/saturated aqueous NH₄Cl mixture. Extraction is carried out withether and then the organic phases are combined, dried with sodiumsulfate, filtered and concentrated under limited vacuum. Finally,(±)-1-methoxy-2-methyl-3-butyn-2-ol is obtained in the form of a brownoil weighing 38 g (quantitative crude yield) which is used withoutsubsequent purification in the following stage.

17.5 ml of the 1.0M solution of potassium tert-butoxide intetrahydrofuran (Aldrich; 17.52 mmol) are added to a solution, cooledwith an ice bath, of 2 g of (±)-1-methoxy-2-methyl-3-butyn-2-ol (17.52mmol) in 6 ml of tetrahydrofuran. Stirring is carried out at ambienttemperature for 30 minutes and then 0.55 ml of methyl iodide (35.04mmol) is added. The reaction mixture is stirred at ambient temperaturefor 3 hours and then is diluted with ether and water. After separationby settling, the organic phase is washed with water, dried over sodiumsulfate, filtered and concentrated under limited vacuum. 2.4 g of theexpected product are obtained in the form of a yellow oil comprisingresidual ether and residual tetrahydrofuran. The(±)-3,4-dimethoxy-3-methylbut-1-yne obtained is used in the followingstage without subsequent purification.

1.8:(±)-2-Amino-7-(3,4-dimethoxy-3-methylbut-1-yn-1-yl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

A suspension of 1.5 g (5.34 mmol) of2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamidein 30 ml of a DMF/Et₃N (v/v; 2/1) mixture is placed in an 80 mlmicrowave tube. Argon is sparged into this suspension for 10 minutes andthen 1.37 g of (±)-3,4-dimethoxy-3-methylbut-1-yne (10.69 mmol), 0.101 gof CuI (0.53 mmol) and 0.187 g ofbis(triphenylphosphine)palladium(II)dichloride (0.27 mmol) aresuccessively added.

The sealed tube is placed in the microwave oven (CEM device, Discovermodel) and the mixture is heated under pressure at 80° C. for 45 minutes(P=100 W) and then cooled and evaporated to dryness. The residue istaken up in ethyl acetate and water. The aqueous phase is extracted withethyl acetate (3 times) and then the organic phases are combined, driedover sodium sulfate, filtered and concentrated under vacuum.

The residue obtained is purified by chromatography on a silica column(solid deposit; elution with a dichloromethane:methanol 100:0 to 98:2gradient). 1.37 g of the expected product are obtained in the form of apale gray powder.

Melting point=185-187° C. MH⁺=373. Yield=69%.

¹H NMR (d₆-DMSO, 400 MHz, δ in ppm): δ 11.75 (s, <1H, very broad); 11.00(q, 1H, broad); 8.45 (d, 1H); 8.00 (s, 1H, broad); 7.4 (d, 1H); 5.8 (s,1H); 4.4 (q, 2H); 3.5-3.3 (m+s, 5H); 2.8 (d, 3H); 1.45 (s, 3H); 1.2 (t,3H).

EXAMPLE 2 Methyl{3-[7-amino-8-ethyl-6-(methylcarbamoyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-yl]prop-2-yn-1-yl}carbamate(compound No. 2) 2.1: Methyl (prop-2-yn-1-yl)carbamate

A solution of 1.3 ml of propargylamine (18.95 mmol, Aldrich) in 19 ml ofdioxane is cooled to 0° C. and then 19 ml of a saturated aqueous NaHCO₃solution are added. Stirring is carried out at 0° C. for 30 minutes andthen 1.83 ml of methyl chloroformate (23.68 mmol) are added. Thereaction mixture is stirred overnight while allowing the temperature togradually return to ambient temperature. The mixture is extracted 4times with ether and then the organic phases are combined, dried oversodium sulfate, filtered and concentrated under vacuum. 1.93 g of theexpected product are obtained in the form of a yellow oil (yield=90%)which is used without subsequent purification.

2.2: Methyl{3-[7-amino-8-ethyl-6-(methylcarbamoyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-yl]prop-2-yn-1-yl}carbamate

A suspension of 0.8 g (2.85 mmol) of2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamidein 22 ml of a DMF/Et₃N (v/v; 2.2/1) mixture is placed in a 10 mlmicrowave tube. Argon is sparged into this suspension for 10 minutes andthen 0.98 g of methyl (prop-2-yn-1-yl)carbamate (8.66 mmol), 0.076 g ofCuI (0.40 mmol) and 0.139 g ofbis(triphenylphosphine)palladium(II)dichloride (0.20 mmol) aresuccessively added.

The sealed tube is placed in the microwave oven (CEM device, Discovermodel) and the mixture is heated under pressure at 90° C. for 15 minutes(P=50 W). After returning to ambient temperature, the mixture isevaporated to dryness and then the residue is taken up in ethyl acetate.The organic phase is washed successively with saturated aqueous NaHCO₃and then with saturated aqueous NaCl. The insoluble material isseparated and subsequently triturated from methanol, tetrahydrofuran andether. 0.284 g of a solid is obtained and is purified by chromatographyon a silica column (solid deposit after dissolving in atetrahydrofuran/methanol mixture and then elution with adichloromethane:methanol 100:0 to 98:2 gradient). 0.095 g of theexpected product is obtained in the form of a white solid.

Melting point=255° C. MH⁺=357. Yield=9.3%.

¹H NMR (d₆-DMSO, 400 MHz, δ in ppm): δ 11.70 (s, <1H, very broad); 11.00(q, 1H, broad); 8.40 (d, 1H); 8.00 (s, 1H, broad); 7.75 (t, 1H, broad);7.40 (d, 1H); 4.40 (q, 2H); 4.10 (d, 2H); 3.55 (s, 3H); 2.80 (d, 3H);1.20 (t, 3H).

EXAMPLE 32-Amino-7-(3-amino-3-methylbut-1-yn-1-yl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamidehydrochloride (compound No. 4)

A suspension of 0.84 g (3.0 mmol) of2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamidein 20 ml of a DMF/Et₃N (v/v; 7/3) mixture is placed in a 10 ml microwavetube. Nitrogen is sparged into this suspension for 10 minutes and then0.50 g of 2-methylbut-3-yn-2-amine (6.0 mmol), 0.089 g of CuI (0.47mmol) and 0.149 g of bis(triphenylphosphine)palladium(II)dichloride(0.21 mmol) are successively added.

The sealed tube is placed in the microwave oven (CEM device, Discovermodel) and the mixture is heated under pressure at 90° C. for 15 minutes(P=50 W) and then at 100° C. for 25 minutes. After returning to ambienttemperature, the mixture is evaporated to dryness and then the residueis taken up in ethyl acetate. The organic phase is washed successivelywith saturated aqueous NaHCO₃ and then with saturated aqueous NaCl,dried over sodium sulfate, filtered and concentrated under vacuum. Theoily residue obtained is purified by chromatography on a silica column(elution with a dichloromethane:methanol 100:0 to 97:3 gradient). 0.151g (0.46 mmol) of the expected product is obtained. This product isdissolved in 3 ml of ethyl acetate and then 0.13 ml (0.52 mmol) of a 4Nsolution of hydrochloric acid in dioxane is added. After filtering anddrying in the oven under vacuum, 0.134 mg of expected product isobtained in the form of a yellow solid.

Melting point=293° C. MH⁺=310. Yield=12%.

¹H NMR (d₆-DMSO, 400 MHz, δ in ppm): δ 11.75 (s, <1H, very broad); 11.00(q, 1H, broad); 8.40 (d, 1H); 8.10 (s, <1H, broad); 7.45 (d, 1H); 4.40(q, 2H); 3.50 (dd, 2H); 3.35 (s, 6H); 2.85 (d, 3H); 1.45 (s, 3H); 1.20(t, 3H).

EXAMPLE 42-Amino-7-[3-(2-amino-2-oxoethoxy)-3-methylbut-1-yn-1-yl]-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide(compound No. 6) 4.1: Ethyl [(1,1-dimethylprop-2-yn-1-yl)oxy]acetate

A solution of 0.87 g (10.32 mmol) of 2-methylbut-3-yn-2-ol in 20 ml ofanhydrous THF is cooled to 0-5° C. with an ice bath and then 10.32 ml(10.32 mmol) of 1.0M potassium t-butoxide in THF (Aldrich) are added.Stirring is carried out under cold conditions for 10 minutes and then1.89 g (11.35 mmol) of ethyl bromoacetate are added. The reactionmixture is stirred at ambient temperature for 45 minutes and then 0.1 Naqueous HCl and ether are added. The organic phase is dried over sodiumsulfate, filtered and concentrated under vacuum. 1.45 g of the expectedproduct are obtained in the form of a yellow oil which is used withoutsubsequent purification. Yield=83%.

4.2: Ethyl({3-[7-amino-8-ethyl-6-(methylcarbamoyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-yl]-1,1-dimethylprop-2-yn-1-yl}oxy)acetate

1.15 g (4.10 mmol) of2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamideand 1.39 g (8.19 mmol) of ethyl [(1,1-dimethylprop-2-yn-1-yl)oxy]acetateare placed in a mixture of 10 ml of dimethylformamide and 10 ml oftriethylamine. Argon is sparged into the reaction mixture for 15 minutesand then 0.031 g (0.16 mmol) of CuI and 0.144 g (0.20 mmol) ofbis(triphenylphosphine)palladium(II)dichloride are successively added.The reaction mixture is heated at 90° C. for 15 hours. After returningto ambient temperature, the reaction mixture is poured onto a water/icemixture. After separating them by settling, the black gum obtained isdissolved in ethyl acetate and then washed with water. The organic phaseis dried over sodium sulfate, filtered and concentrated under vacuum.1.4 g of a brown oil are obtained, which oil is purified bychromatography on silica (elution with a cyclohexane/ethyl acetate 30:70to 20:80 gradient) to give 0.72 g of the expected product in the form ofa yellow solid.

Yield=41%.

4.3:2-Amino-7-[3-(2-amino-2-oxoethoxy)-3-methylbut-1-yn-1-yl]-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

0.30 g (0.72 mmol) of ethyl({3-[7-amino-8-ethyl-6-(methylcarbamoyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-yl]-1,1-dimethylprop-2-yn-1-yl}oxy)acetate is placed in 30 ml of methanol in a 50 ml sealed tube. Thesolution is cooled with an ice bath and gaseous ammonia is sparged in tosaturation. Heating is carried out at 80° C. for 8 hours and then themixture is evaporated to dryness. The residue obtained is purified bychromatography on a silica column (solid deposit after dissolving in atetrahydrofuran/methanol mixture and then elution with adichloromethane:methanol 100:0 to 95:5 gradient) to give 0.18 g of theexpected product in the form of a white solid

Melting point=204° C. MH⁺=386. Yield=64%.

¹H NMR (d₆-DMSO, 400 MHz, δ in ppm): δ 11.85 (s, <1H, very broad); 11.00(q, 1H, broad); 8.45 (d, 1H); 7.45 (d, 1H); 7.20 (d, <2H, broad); 4.40(q, 2H); 3.95 (s, 2H); 2.80 (d, 3H); 1.60 (s, 6H); 1.20 (t, 3H).

The chemical structures and the physical properties of a few compoundsof formula (I) according to the invention are illustrated in thefollowing table. In this table:

-   -   Me and Et respectively represent methyl and ethyl groups,    -   in the “salt” column, “-” represents a compound in the form of        the free base, while “HCl” represents a compound in the form of        the hydrochloride,    -   the M.p. column indicates the melting point, in ° C., of the        compound, and    -   in the LC/MS column, the high performance liquid chromatography        analytical method used (A or B) and described in detail below,        the retention time of the compound, expressed in minutes, and        the MH⁺ peak identified by mass spectrometry are successively        indicated.

Method A:

Column: Gemini, 50×3 mm, 3 μm

Solvent A: H₂O+0.1% HCO₂H; solvent B: ACN+0.1% HCO₂H; flow rate=1 ml/min

Gradient: 95/5 (0 min) to 0/100 (5.5 min) to 0/100 (7.5 min)

Detection: 220 nM

Ionization: ESI+

Method B:

Column: Kromasil, 50×2.1 mm, 3.5 μm

Solvent A: CH₃CO₂NH₄ 5 mM; solvent B: ACN; flow rate=0.5 ml/min

Gradient: 100/0 (0 min) to 0/100 (13 min) to 0/100 (16 min)

Detection: 220 nM

Ionization: ESI+

-   -   in the chirality column “/” represents an achiral compound and        (±) represents a compound in the form of the racemic mixture.

TABLE (I)

No. R₁ R₂ R₃ R₄ Y Salt LC/MS M.p. Chirality 1 Me

Et Me OMe — B  6.16 373 185-187 (±) 2 H H Et Me

— B  3.48 358 250 / 3 H H Et Me

— C  4.94 342 239 / 4 Me Me Et Me NH₂ HCl B 293 /  4.08 327 5 H H Et MeOMe — C 233 /  6.8 315 6 Me Me Et Me

— B  3.83 386 204 /

The compounds according to the invention have formed the subject ofpharmacological assays which make it possible to determine theirinhibitory effect on the VEGFR-3 enzyme.

Measurement of the Tyrosine Kinase Activity of VEGFR-3 by ELISA

The enzymatic activity of VEGFR-3 is evaluated on an ELISA assay bymeasuring the intensity of phosphorylation of the substrate polyGlu-Tyr. The effect of the products is quantified by the concentrationwhich decreases the total activity of the enzyme by 50% (IC₅₀). For thedetermination of the IC₅₀ values, the product is diluted in DMSO with aconcentration range which extends from 3 to 1000 nM. The day before themanipulation, 125 μl of the poly Glu-Tyr substrate (250 μg/ml in 1×PBSwithout Ca²⁺ or Mg²⁺ or sodium bicarbonate) are deposited in each wellof an ELISA plate (for example, an ELISA plate of the SIGMA ProteinTyrosine Kinase Assay kit, Ref. PTK-101). The plate is subsequentlycovered with an adhesive film and incubated overnight at 37° C. Thefollowing day, the wells are emptied by turning the plate over, washedby adding 300 μl of buffer solution (PBS+0.05% Tween 20) and dried byfurther incubation of the plate for 2 h at 37° C. A 90 μl reactionmixture is deposited onto each well. This mixture comprises the 1×kinase buffer to which 30 μM of ATP and the inhibitor at the desiredconcentration have been added. Subsequently, 20 μl of VEGFR-3-TK (CellSignaling, Ref. 7790), diluted beforehand in the kinase buffer withoutATP, are added (with the exception of the negative control wells, where20 μl of buffer without enzyme are added). The plates are subsequentlyincubated for 30 min at ambient temperature with gentle agitation. After3 rinses with the buffer solution (300 μl/well per wash), 100 μl ofanti-phosphotyrosine—HRP antibody ( 1/30 000) are added to each well andthe plates are again incubated for 30 min at ambient temperature withgentle agitation. After 3 washes in buffer solution (300 μl/well perwash), the phosphorylation of the substrate is revealed by adding 100 μlper well of OPD substrate, 1 OPD tablet and 1 urea tablet in 20 ml ofwater (extemporaneous preparation in the dark). After incubation for 7minutes at ambient temperature and in the dark, the reaction is stoppedby adding 100 μl of 1.25 M (2.5N) H₂SO₄ per well, and the absorbance isread at 492 nm. The total activity is evaluated by the difference inoptical density obtained on samples incubated in the presence(stimulated) and in the absence (non-stimulated) of VEGFR-3.

The compounds in accordance with the invention exhibit IC₅₀ values ofless than 10 μM, for the most part of less than 1 μM. By way ofexamples, compounds Nos 4 and 5 of the table exhibit IC₅₀ values of 451nM and 343 nM respectively.

It is thus apparent that the compounds according to the invention havean inhibitory activity on the VEGFR-3 enzyme; they can thus be used inthe preparation of medicaments, in particular of medicaments which areVEGFR-3 inhibitors.

Thus, according to another of its aspects, a subject matter of theinvention is medicaments which comprise a compound of formula (I), or anaddition salt of the latter with a pharmaceutically acceptable acid orbase, or even a hydrate or a solvate, and also an enantiomer or adiastereoisomer, including their mixture, of the compound of formula(I).

Another aspect of the invention comprises a combination of at least onecompound according to the invention and at least one chemotherapy agent.

Specifically, the compounds of the present invention can be used, aloneor as a mixture, with at least one chemotherapy agent which can bechosen from:

-   -   alkylating agents,    -   intercalating agents,    -   antimicrotubule agents,    -   antimitotic agents,    -   antimetabolites,    -   antiproliferative agents,    -   antibiotics,    -   immunomodulatory agents,    -   anti-inflammatories,    -   kinase inhibitors,    -   antiangiogenic agents,    -   antivascular agents,    -   estrogenic and androgenic hormones,        and the prodrugs of the abovementioned agents or derivatives.

It is also possible to combine the compounds according to the inventionwith a radiation treatment.

The combinations of the compounds of the invention with the chemotherapyagents mentioned above and/or the radiation are another subject matterof the present invention.

The chemotherapy agents mentioned above and/or the radiation can beadministered simultaneously, separately or sequentially. The treatmentwill be adjusted by the practitioner according to the patient to betreated.

These medicaments are used therapeutically, in particular in thetreatment and prevention:

-   -   of cancers and metastases thereof, such as: glioblastomas,        multiple myelomas, myelodysplasic syndromes, Kaposi's sarcomas,        solid tumors, lymphomas, melanomas, breast cancers, colorectal        cancers, lung cancers, including non-small-cell cancers,        pancreatic cancers, prostate cancers, kidney cancers, head and        neck cancers, liver cancers, ovarian cancers, cancers of the        respiratory tract and chest, tumor angiogeneses or other tumors        expressing VEGFR-3 or involving a process of angiogenesis or of        lymphangiogenesis,    -   non-oncological proliferative diseases and pathological        angiogenesis linked to VEGFR-3, such as: arthroses, restenoses,        psoriasis, hemangiomas, glaucomas, glomerulonephritis, diabetic        nephropathies, nephrosclerosis, thrombotic microangiopathic        syndromes, liver cirrhosis, atherosclerosis, organ transplant        rejection, or eye diseases involving a process of angiogenesis        or of lymphangiogenesis, such as diabetic retinopathy or macular        degeneration,    -   or also in the treatment and prevention of inflammation (chronic        or non-chronic), of infection by microorganisms and of        autoimmune diseases, such as rheumatoid arthritis,    -   or also in the treatment of rare diseases, such as        lymphangioleiomyomatosis.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions comprisean effective dose of at least one compound according to the invention,or a pharmaceutically acceptable salt, a hydrate or a solvate of saidcompound, and at least one pharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and themethod of administration desired, from the usual excipients known to aperson skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its optional salt, solvate orhydrate, can be administered in unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and human beingsfor the treatment or prevention of the above disorders or diseases.

The appropriate unit administration forms comprise oral forms, such astablets, soft or hard gelatin capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, intratracheal, intraocularand intranasal administration forms, forms for administration byinhalation, topical, transdermal, subcutaneous, intramuscular orintravenous administration forms, rectal administration forms andimplants. The compounds according to the invention can be used, fortopical application, in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the tablet form can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium  6.0 mg Corn starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

The present invention, according to another of its aspects, also relatesto a method for the treatment of the pathologies indicated above whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention or one of its pharmaceuticallyacceptable salts or its hydrates or its solvates.

What is claimed is:
 1. A method treating a disease selected from thegroup consisting of restenosis, nephrosclerosis, and liver cirrhosis,comprising administering to a patient in need thereof an effective doseof a compound of formula (I):

wherein: R₁ and R₂ represent, independently of one another: a hydrogenatom, or a C₁-C₇ alkyl group optionally substituted by one or morealkoxy groups; R₃ represents a C₁-C₇ alkyl group; R₄ represents ahydrogen atom or a C₁-C₄ alkyl group; Y represents a C₁-C₄ alkoxy groupor an —NRR′ or —O(CH₂)_(n)—C(O)—NRR′ group where R and R′ are as definedbelow and n is an integer equal to 1 or 2; R″ represents a C₁-C₄ alkylgroup; and R and R′ represent, independently of one another, a hydrogenatom, a —CO—(C₁-C₄ alkyl) group or a —COOR″ group, where R″ is asdefined above; or an acid addition salt thereof, or an enantiomer ordiastereoisomer thereof, or a mixture thereof.
 2. The method accordingto claim 1 wherein the disease is restinosis.
 3. The method according toclaim 1 or 2, wherein Y represents a C₁-C₄-alkoxy group; or an acidaddition salt thereof, or an enantiomer or diastereoisomer thereof, or amixture thereof.
 4. The method according to claim 1 or 2, wherein Yrepresents an —NRR′ group, or an acid addition salt thereof, or anenantiomer or diastereoisomer thereof, or a mixture thereof.
 5. Themethod according to claim 1 or 2, wherein Y represents an—O(CH₂)_(n)—C(O)—NRR′ group n is an integer equal to 1 or 2; or an acidaddition salt thereof, or an enantiomer or diastereoisomer thereof, or amixture thereof.
 6. The method according to claim 1 or 2, where thecompound is selected from the group consisting of:(±)-2-amino-7-(3,4-dimethoxy-3-methylbut-1-yn-1-yl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;2-amino-7-[3-(2-amino-2-oxoethoxy)-3-methylbut-1-yn-1-yl]-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;and2-amino-1-ethyl-7-(3-methoxyprop-1-yn-1-yl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;or an acid addition salt thereof.
 7. The method according to claim 1 or2 wherein R₁ and R₂ are hydrogen, R₃ is ethyl, R₄ is methyl and Y is

or an acid addition salt thereof.
 8. The method according to claim 1 or2 where R₁, R₂ and R₄ is methyl, R₃ is ethyl and Y is NH₂ or an acidaddition salt thereof.